Alkene piperidine derivatives as antiviral agents

ABSTRACT

This disclosure provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the disclosure is concerned with alkene piperidine derivatives that possess unique antiviral activity. More particularly, the present disclosure relates to compounds useful for the treatment of HIV and AIDS.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 60/811,898 filed Jun. 8, 2006.

FIELD OF THE DISCLOSURE

This disclosure provides compounds having drug and bio-affectingproperties, their pharmaceutical compositions and method of use. Inparticular, the disclosure is concerned with alkene piperidinederivatives that possess unique antiviral activity. More particularly,the present disclosure relates to compounds useful for the treatment ofHIV and AIDS.

BACKGROUND ART

HIV-1 (human immunodeficiency virus-1) infection remains a major medicalproblem, with an estimated 40 million people infected worldwide at theend of 2005. The number of cases of HIV and AIDS (acquiredimmunodeficiency syndrome) has risen rapidly. In 2005, approximately 5.0million new infections were reported, and 3.1 million people died fromAIDS. Currently available drugs for the treatment of HIV includenucleoside reverse transcriptase (RT) inhibitors or approved single pillcombinations: zidovudine (or AZT or Retrovir®), didanosine (or Videx®),stavudine (or Zerit®), lamivudine (or 3TC or Epivir®), zalcitabine (orDDC or Hivid®), abacavir succinate (or Ziagen®), Tenofovir disoproxilfumarate salt (or Viread®), emtricitabine (or FTC), Combivir® (contains−3TC plus AZT), Trizivir® (contains abacavir, lamivudine, andzidovudine), Epzicom® (contains abacavir and lamivudine), Truvada®(contains Viread® and emtricitabine); non-nucleoside reversetranscriptase inhibitors: nevirapine (or Viramune®), delavirdine (orRescriptor®) and efavirenz (or Sustiva®), and peptidomimetic proteaseinhibitors or approved formulations: saquinavir, indinavir, ritonavir,nelfinavir, amprenavir, lopinavir, and Kaletra® (lopinavir andRitonavir). Each of these drugs can only transiently restrain viralreplication if used alone. However, when used in combination, thesedrugs have a profound effect on viremia and disease progression. Infact, significant reductions in death rates among AIDS patients havebeen recently documented as a consequence of the widespread applicationof combination therapy. However, despite these impressive results, 30 to50% of patients ultimately fail combination drug therapies. Insufficientdrug potency, non-compliance, restricted tissue penetration anddrug-specific limitations within certain cell types (e.g. mostnucleoside analogs cannot be phosphorylated in resting cells) mayaccount for the incomplete suppression of sensitive viruses.Furthermore, the high replication rate and rapid turnover of HIV-1combined with the frequent incorporation of mutations, leads to theappearance of drug-resistant variants and treatment failures whensub-optimal drug concentrations are present. Therefore, novel anti-HIVagents exhibiting distinct resistance patterns, and favorablepharmacokinetic as well as safety profiles are needed to provide moretreatment options. Improved HIV fusion inhibitors and HIV entrycoreceptor antagonists are two examples of new classes of anti-HIVagents currently being studied by a number of investigators.

The properties of a class of HIV entry inhibitors called HIV attachmentinhibitors has been improved in an effort to obtain compounds withmaximized utility and efficacy as antiviral agents. A disclosuredescribing indoles of which the structure shown below for BMS-705 isrepresentative has been disclosed [Antiviral Indoleoxoacetyl piperazineDerivatives].

Two other compounds, referred to in the literature as BMS-806 andBMS-043 have been described in both the academic and patent art:

Some description of their properties in human clinical trials have beendisclosed in literature.

It should be noted that in all three of these structures, a piperazineamide (In these three structures a piperazine phenyl amide) is presentand this group is directly attached to an oxoacetyl moiety. Theoxoacetyl group is attached at the 3-position of 4-Fluoro indole inBMS-705 and to the 3 position of substituted azaindoles in BMS-806 andBMS-043.

In an effort to obtain improved anti-HIV compounds, later publicationsdescribed in part, modified substitution patterns on the indoles andazaindoles. Examples of such effort include: (1) novel substitutedindoleoxoacetic piperazine derivatives, (2) substitutedpiperazinyloxoacetylindole derivatives, and (3) substitutedazaindoleoxoacetic piperazine derivatives.

Replacement of these groups with other heteraromatics or substitutedheteroaroamatics or bicyclic hydrocarbons was also shown to be feasible.Examples include: (1) indole, azaindole and related heterocyclicamidopiperazine derivatives; (2) bicyclo 4.4.0 antiviral derivatives;and (3) diazaindole derivatives.

A select few replacements for the piperazine amide portion of themolecules have also been described in the art and among these examplesare (1) some piperidine alkenes; (2) some pyrrolidine amides; (3) someN-aryl or heteroaryl piperazines; (4) some piperazinyl ureas; and (5)some carboline containing compounds.

Antiviral compounds containing piperidine alkenes are contained in thefollowing published patent applications Wang, Tao; et. al. U.S. Pat.Appl. Publ. US 20040186292 A1 and Wang, et. al. U.S. Pat. Appl. Publ. US20040063744 A1 but are structurally distinct from the compounds in thisapplication.

Method(s) for preparing prodrugs for this class of compounds wasdisclosed in Prodrugs of Piperazine and Substituted Piperidine AntiviralAgents (Ueda et al., U.S. non-provisional application Ser. No.11/066,745, filed Feb. 25, 2005 or US20050209246A1 or WO2005090367A1).

A published PCT patent application WO2003103607A1 (Jun. 11, 2003)disclosures an assay useful for assaying some HIV inhibitors.

Several published patent applications describe combination studies withpiperazine benzamide inhibitors, for example, US20050215543(WO2005102328A1), US20050215544 (WO2005102391A1), and US20050215545(WO2005102392A2).

A publication on new compounds in this class of attachment inhibitors(Jinsong Wang et. al. Org. Biol. Chem. 2005, 3, 1781-1786.) and a patentapplication on some more remotely related compounds have appearedWO2005/016344 published on Feb. 24, 2005.

Published patent applications WO2005/016344 and WO2005/121094 alsodescribe piperazine derivatives which are HIV inhibitors. The compoundsdescribed in these applications are structurally distinct from thecompounds of the present disclosure.

Nothing in these references can be construed to disclose or suggest thenovel compounds of this disclosure and their use to inhibit HIVinfection.

SUMMARY OF THE DISCLOSURE

The present disclosure relates to compounds of Formula I, thepharmaceutically acceptable salts and/or solvates (e.g., hydrates)thereof, their pharmaceutical formulations, and their use in patientssuffering from or susceptible to a virus such as HIV. The compounds ofFormula I, their pharmaceutically acceptable salts and/or solvate areeffective anticiral agents, particularly as inhibitors of HIV. They areuseful for the treatment of HIV and AIDS.

A first embodiment of the disclosure are compounds of Formula I,including pharmaceutically acceptable salts thereof,

wherein:

-   A is quinoline, isoquinoline, quinazolinyl, phenyl, indazolyl,    benzoxazolyl, or pyridyl wherein said, isoquinoline, quinazolinyl,    phenyl, indazolyl, benzoxazolyl, or pyridyl is substituted with from    1 to 3 substituents selected from C₁₋₆ alkoxy, —COOC₁₋₃ alkyl, C₁₋₆    alkyl, COONH₂, CON(COOC₁₋₃ alkyl)₂, COONHC₁₋₃ alkyl, —NHCH₂CH₂OH,    N(C₁₋₃ alkyl)₂, NH(C₁₋₃ alkyl), halogen, or pyazolyl;-   R⁹-R¹⁶ are independently hydrogen or methyl with the proviso that no    more than three are methyl and none are geminal (on the same    carbon);-   B is CN, C(O)NH₂, F, Cl, phenyl, oxazolyl, isozazolyl, pyrazolyl or    oxadiazolyl wherein said phenyl, oxazolyl, isozazolyl, pyrazolyl or    oxadiazolyl is optionally substituted with 1 to 2 halogen, amino,    dimethyl amino, methylamino, or C₁₋₃ alkyl;-   E is phenyl, pyridyl, or pyrimidinyl;-   Z is methyl where the configuration at the carbon where it is    attached is either (S), (R), or a mixture of the two configurations.

Another embodiment of the present disclosure is a method for treatingmammals infected with a virus, especially wherein said virus is HIV,comprising administering to said mammal an antiviral effective amount ofa compound of Formula I, and one or more pharmaceutically acceptablecarriers, excipients or diluents; optionally the compound of Formula Ican be administered in combination with an antiviral effective amount ofan AIDS treatment agent selected from the group consisting of: (a) anAIDS antiviral agent; (b) an anti-infective agent; (c) animmunomodulator; and (d) HIV entry inhibitors.

Another embodiment of the present disclosure is a pharmaceuticalcomposition comprising an antiviral effective amount of a compound ofFormula I and one or more pharmaceutically acceptable carriers,excipients, diluents and optionally in combination with an antiviraleffective amount of an AIDS treatment agent selected from the groupconsisting of: (a) an AIDS antiviral agent; (b) an anti-infective agent;(c) an immunomodulator; and (d) HIV entry inhibitors.

DETAILED DESCRIPTION OF THE DISCLOSURE

Since the compounds of the present disclosure, may possess asymmetriccenters and therefore occur as mixtures of diastereomers andenantiomers, the present disclosure includes the individualdiastereoisomeric and enantiomeric forms of the compounds of Formula Iin addition to the mixtures thereof.

Definitions

The term “C₁₋₆ alkyl” as used herein and in the claims (unless specifiedotherwise) mean straight or branched chain alkyl groups such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl and thelike.

“Halogen” refers to chlorine, bromine, iodine or fluorine.

An “aryl” group refers to an all carbon monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of carbon atoms)groups having a completely conjugated pi-electron system. Examples,without limitation, of aryl groups are phenyl, napthalenyl andanthracenyl. The aryl group may be substituted or unsubstituted. Whensubstituted the substituted group(s) is preferably one or more selectedfrom alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy,thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen,nitro, carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido, aminoand —NR^(x)R^(y), wherein R^(x) and R^(y) are independently selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl, aryl,carbonyl, C-carboxy, sulfonyl, trihalomethyl, and, combined, a five- orsix-member heteroalicyclic ring.

As used herein, a “heteroaryl” group refers to a monocyclic or fusedring (i.e., rings which share an adjacent pair of atoms) group having inthe ring(s) one or more atoms selected from the group consisting ofnitrogen, oxygen and sulfur and, in addition, having a completelyconjugated pi-electron system. Unless otherwise indicated, theheteroaryl group may be attached at either a carbon or nitrogen atomwithin the heteroaryl group. It should be noted that the term heteroarylis intended to encompass an N-oxide of the parent heteroaryl if such anN-oxide is chemically feasible as is known in the art. Examples, withoutlimitation, of heteroaryl groups are furyl, thienyl, benzothienyl,thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl,benzothiazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,pyrrolyl, pyranyl, tetrahydropyranyl, pyrazolyl, pyridyl, pyrimidinyl,quinolinyl, isoquinolinyl, purinyl, carbazolyl, benzoxazolyl,benzimidazolyl, indolyl, isoindolyl, pyrazinyl, diazinyl, pyrazine,triazinyl, tetrazinyl, and tetrazolyl. When substituted the substitutedgroup(s) is preferably one or more selected from alkyl, cycloalkyl,aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thioalkoxy, thiohydroxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro,carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido,amino, and —NR^(x)R^(y), wherein R^(x) and R^(y) are as defined above.

As used herein, a “heteroalicyclic” group refers to a monocyclic orfused ring group having in the ring(s) one or more atoms selected fromthe group consisting of nitrogen, oxygen and sulfur. Rings are selectedfrom those which provide stable arrangements of bonds and are notintended to encomplish systems which would not exist. The rings may alsohave one or more double bonds. However, the rings do not have acompletely conjugated pi-electron system. Examples, without limitation,of heteroalicyclic groups are azetidinyl, piperidyl, piperazinyl,imidazolinyl, thiazolidinyl, 3-pyrrolidin-1-yl, morpholinyl,thiomorpholinyl and tetrahydropyranyl. When substituted the substitutedgroup(s) is preferably one or more selected from alkyl, cycloalkyl,aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro,carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy,sulfinyl, sulfonyl, sulfonamido, trihalomethanesulfonamido,trihalomethanesulfonyl, silyl, guanyl, guanidino, ureido, phosphonyl,amino and —NR^(x)R^(y), wherein R^(x) and R^(y) are as defined above.

An “alkyl” group refers to a saturated aliphatic hydrocarbon includingstraight chain and branched chain groups. Preferably, the alkyl grouphas 1 to 20 carbon atoms (whenever a numerical range; e.g., “1-20”, isstated herein, it means that the group, in this case the alkyl group maycontain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to andincluding 20 carbon atoms). More preferably, it is a medium size alkylhaving 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having1 to 4 carbon atoms. The alkyl group may be substituted orunsubstituted. When substituted, the substituent group(s) is preferablyone or more individually selected from trihaloalkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy,heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl,sulfonamido, trihalomethanesulfonamido, trihalomethanesulfonyl, andcombined, a five- or six-member heteroalicyclic ring.

A “cycloalkyl” group refers to an all-carbon monocyclic or fused ring(i.e., rings which share and adjacent pair of carbon atoms) groupwherein one or more rings does not have a completely conjugatedpi-electron system. Examples, without limitation, of cycloalkyl groupsare cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane,cyclohexadiene, cycloheptane, cycloheptatriene and adamantane. Acycloalkyl group may be substituted or unsubstituted. When substituted,the substituent group(s) is preferably one or more individually selectedfrom alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl,sulfonamido, trihalo-methanesulfonamido, trihalomethanesulfonyl, silyl,guanyl, guanidino, ureido, phosphonyl, amino and —NR^(x)R^(y) with R^(x)and R^(y) as defined above.

An “alkenyl” group refers to an alkyl group, as defined herein, havingat least two carbon atoms and at least one carbon-carbon double bond.

An “alkynyl” group refers to an alkyl group, as defined herein, havingat least two carbon atoms and at least one carbon-carbon triple bond.

A “hydroxy” group refers to an —OH group.

An “alkoxy” group refers to both an —O-alkyl and an —O-cycloalkyl groupas defined herein.

An “aryloxy” group refers to both an —O-aryl and an —O-heteroaryl group,as defined herein.

A “heteroaryloxy” group refers to a heteroaryl-O— group with heteroarylas defined herein.

A “heteroalicycloxy” group refers to a heteroalicyclic-O— group withheteroalicyclic as defined herein.

A “thiohydroxy” group refers to an —SH group.

A “thioalkoxy” group refers to both an S-alkyl and an —S-cycloalkylgroup, as defined herein.

A “thioaryloxy” group refers to both an —S-aryl and an —S-heteroarylgroup, as defined herein.

A “thioheteroaryloxy” group refers to a heteroaryl-S— group withheteroaryl as defined herein.

A “thioheteroalicycloxy” group refers to a heteroalicyclic-S— group withheteroalicyclic as defined herein.

A “carbonyl” group refers to a —C(═O)—R″ group, where R″ is selectedfrom the group consisting of hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheteroalicyclic (bonded through a ring carbon), as each is definedherein.

An “aldehyde” group refers to a carbonyl group where R″ is hydrogen.

A “thiocarbonyl” group refers to a —C(═S)—R″ group, with R″ as definedherein.

A “Keto” group refers to a —CC(═O)C— group wherein the carbon on eitheror both sides of the C═O may be alkyl, cycloalkyl, aryl or a carbon of aheteroaryl or heteroaliacyclic group.

A “trihalomethanecarbonyl” group refers to a Z₃CC(═O)— group with said Zbeing a halogen.

A “C-carboxy” group refers to a —C(═O)O—R″ groups, with R″ as definedherein.

An “O-carboxy” group refers to a R″C(—O)O-group, with R″ as definedherein.

A “carboxylic acid” group refers to a C-carboxy group in which R″ ishydrogen.

A “trihalomethyl” group refers to a —CZ₃, group wherein Z is a halogengroup as defined herein.

A “trihalomethanesulfonyl” group refers to an Z₃CS(═O)₂— groups with Zas defined above.

A “trihalomethanesulfonamido” group refers to a Z₃CS(═O)₂NR^(x)— groupwith Z as defined above and R^(x) being H or (C₁₋₆)alkyl.

A “sulfinyl” group refers to a —S(═O)—R″ group, with R″ being(C₁₋₆)alkyl.

A “sulfonyl” group refers to a —S(═O)₂R″ group with R″ being(C₁₋₆)alkyl.

A “S-sulfonamido” group refers to a —S(═O)₂NR^(X)R^(Y), with R^(X) andR^(Y) independently being H or (C₁₋₆)alkyl.

A “N-Sulfonamido” group refers to a R″S(═O)₂NR_(X)— group, with R_(x)being H or (C₁₋₆)alkyl.

A “O-carbamyl” group refers to a —OC(═O)NR^(x)R^(y) group, with R^(X)and R^(Y) independently being H or (C₁₋₆)alkyl.

A “N-carbamyl” group refers to a R^(x)OC(═O)NR^(y) group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

A “O-thiocarbamyl” group refers to a —OC(═S)NR^(x)R^(y) group, withR^(x) and R^(y) independently being H or (C₁₋₆)alkyl.

A “N-thiocarbamyl” group refers to a R^(x)OC(═S)NR^(y)— group, withR^(x) and R^(y) independently being H or (C₁₋₆)alkyl.

An “amino” group refers to an —NH₂ group.

A “C-amido” group refers to a —C(═O)NR^(x)R^(y) group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

A “C-thioamido” group refers to a —C(═S)NR^(x)R^(y) group, with R^(x)and R^(y) independently being H or (C₁₋₆)alkyl.

A “N-amido” group refers to a R^(x)C(═O)NR^(y)— group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

An “ureido” group refers to a —NR^(x)C(═O)NR^(y)R^(y2) group, withR^(x), R^(y), and R^(y2) independently being H or (C₁₋₆)alkyl.

A “guanidino” group refers to a —R^(x)NC(═N)NR^(y)R^(y2) group, withR^(x), R^(y), and R^(y2) independently being H or (C₁₋₆)alkyl.

A “guanyl” group refers to a R^(x)R^(y)NC(═N)— group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

A “cyano” group refers to a —CN group.

A “silyl” group refers to a —Si(R″)₃, with R″ being (C₁₋₆)alkyl orphenyl.

A “phosphonyl” group refers to a P(═O)(OR^(x))₂ with R^(x) being(C₁₋₆)alkyl.

A “hydrazino” group refers to a —NR^(x)NR^(y)R^(y2) group, with R^(x),R^(y), and R^(y2) independently being H or (C₁₋₆)alkyl.

Any two adjacent R groups may combine to form an additional aryl,cycloalkyl, heteroaryl or heterocyclic ring fused to the ring initiallybearing those R groups.

It is known in the art that nitrogen atoms in heteroaryl systems can be“participating in a heteroaryl ring double bond”, and this refers to theform of double bonds in the two tautomeric structures which comprisefive-member ring heteroaryl groups. This dictates whether nitrogens canbe substituted as well understood by chemists in the art. The disclosureand claims of the present disclosure are based on the known generalprinciples of chemical bonding. It is understood that the claims do notencompass structures known to be unstable or not able to exist based onthe literature.

Physiologically acceptable salts and prodrugs of compounds disclosedherein are within the scope of this disclosure. The term“pharmaceutically acceptable salt” as used herein and in the claims isintended to include nontoxic base addition salts. Suitable salts includethose derived from organic and inorganic acids such as, withoutlimitation, hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lacticacid, sulfinic acid, citric acid, maleic acid, fumaric acid, sorbicacid, aconitic acid, salicylic acid, phthalic acid, and the like. Theterm “pharmaceutically acceptable salt” as used herein is also intendedto include salts of acidic groups, such as a carboxylate, with suchcounterions as ammonium, alkali metal salts, particularly sodium orpotassium, alkaline earth metal salts, particularly calcium ormagnesium, and salts with suitable organic bases such as loweralkylamines (methylamine, ethylamine, cyclohexylamine, and the like) orwith substituted lower alkylamines (e.g. hydroxyl-substitutedalkylamines such as diethanolamine, triethanolamine ortris(hydroxymethyl)-aminomethane), or with bases such as piperidine ormorpholine.

In the method of the present disclosure, the term “antiviral effectiveamount” means the total amount of each active component of the methodthat is sufficient to show a meaningful patient benefit, i.e., healingof acute conditions characterized by inhibition of the HIV infection.When applied to an individual active ingredient, administered alone, theterm refers to that ingredient alone. When applied to a combination, theterm refers to combined amounts of the active ingredients that result inthe therapeutic effect, whether administered in combination, serially orsimultaneously. The terms “treat, treating, treatment” as used hereinand in the claims means preventing or ameliorating diseases associatedwith HIV infection.

The present disclosure is also directed to combinations of the compoundswith one or more agents useful in the treatment of AIDS. For example,the compounds of this disclosure may be effectively administered,whether at periods of pre-exposure and/or post-exposure, in combinationwith effective amounts of the AIDS antivirals, immunomodulators,antiinfectives, or vaccines, such as those in the following table.

ANTIVIRALS Drug Name Manufacturer Indication 097 Hoechst/Bayer HIVinfection, AIDS, ARC (non-nucleoside reverse transcriptase (RT)inhibitor) Amprenavir Glaxo Wellcome HIV infection, 141 W94 AIDS, ARC GW141 (protease inhibitor) Abacavir (1592U89) Glaxo Wellcome HIVinfection, GW 1592 AIDS, ARC (RT inhibito Acemannan Carrington Labs ARC(Irving, TX) Acyclovir Burroughs Wellcome HIV infection, AIDS, ARC, incombination with AZT AD-439 Tanox Biosystems HIV infection, AIDS, ARCAD-519 Tanox Biosystems HIV infection, AIDS, ARC Adefovir dipivoxilGilead Sciences HIV infection AL-721 Ethigen ARC, PGL (Los Angeles, CA)HIV positive, AIDS Alpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIVin combination w/Retrovir Ansamycin Adria Laboratories ARC LM 427(Dublin, OH) Erbamont (Stamford, CT) Antibody which Advanced BiotherapyAIDS, ARC Neutralizes pH Concepts Labile alpha aberrant (Rockville, MD)Interferon AR177 Aronex Pharm HIV infection, AIDS, ARC Beta-fluoro-ddANat'l Cancer Institute AIDS-associated diseases BMS-232623 Bristol-MyersSquibb/ HIV infection, (CGP-73547) Novartis AIDS, ARC (proteaseinhibitor) BMS-234475 Bristol-Myers Squibb/ HIV infection, (CGP-61755)Novartis AIDS, ARC (protease inhibitor) CI-1012 Warner-Lambert HIV-1infection Cidofovir Gilead Science CMV retinitis, herpes, papillomavirusCurdlan sulfate AJI Pharma USA HIV infection Cytomegalovirus MedImmuneCMV retinitis Immune globin Cytovene Syntex Sight threateningGanciclovir CMV peripheral CMV retinitis Delaviridine Pharmacia-UpjohnHIV infection, AIDS, ARC (RT inhibitor) Dextran Sulfate Ueno Fine Chem.AIDS, ARC, HIV Ind. Ltd. (Osaka, positive Japan) asymptomatic ddCHoffman-La Roche HIV infection, AIDS, Dideoxycytidine ARC ddIBristol-Myers Squibb HIV infection, AIDS, Dideoxyinosine ARC;combination with AZT/d4T DMP-450 AVID HIV infection, (Camden, NJ) AIDS,ARC (protease inhibitor) Efavirenz Bristol Myers Squibb HIV infection,(DMP 266, Sustiva ®) AIDS, ARC (−)6-Chloro-4-(S)- (non-nucleoside RTcyclopropylethynyl- inhibitor) 4(S)-trifluoro- methyl-1,4-dihydro-2H-3,1-benzoxazin- 2-one, STOCRINE EL10 Elan Corp, PLC HIV infection(Gainesville, GA) Famciclovir Smith Kline herpes zoster, herpes simplexFTC Emory University HIV infection, AIDS, ARC (reverse transcriptaseinhibitor) GS 840 Gilead HIV infection, AIDS, ARC (reverse transcriptaseinhibitor) HBY097 Hoechst Marion HIV infection, Roussel AIDS, ARC(non-nucleoside reverse transcriptase inhibitor) Hypericin VIMRx Pharm.HIV infection, AIDS, ARC Recombinant Human Triton Biosciences AIDS,Kaposi's Interferon Beta (Almeda, CA) sarcoma, ARC Interferon alfa-n3Interferon Sciences ARC, AIDS Indinavir Merck HIV infection, AIDS, ARC,asymptomatic HIV positive, also in combination with AZT/ddI/ddC ISIS2922 ISIS Pharmaceuticals CMV retinitis KNI-272 Nat'l Cancer InstituteHIV-assoc. diseases Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS,ARC (reverse transcriptase inhibitor); also with AZT LobucavirBristol-Myers Squibb CMV infection Nelfinavir Agouron HIV infection,Pharmaceuticals AIDS, ARC (protease inhibitor) Nevirapine BoeheringerHIV infection, Ingleheim AIDS, ARC (RT inhibitor) Novapren NovaferonLabs, Inc. HIV inhibitor (Akron, OH) Peptide T Peninsula Labs AIDSOctapeptide (Belmont, CA) Sequence Trisodium Astra Pharm. CMV retinitis,HIV Phosphonoformate Products, Inc. infection, other CMV infectionsPNU-140690 Pharmacia Upjohn HIV infection, AIDS, ARC (proteaseinhibitor) Probucol Vyrex HIV infection, AIDS RBC-CD4 Sheffield Med. HIVinfection, Tech (Houston, TX) AIDS, ARC Ritonavir Abbott HIV infection,AIDS, ARC (protease inhibitor) Saquinavir Hoffmann- HIV infection,LaRoche AIDS, ARC (protease inhibitor) Stavudine; d4T Bristol-MyersSquibb HIV infection, AIDS, Didehydrodeoxy- ARC thymidine ValaciclovirGlaxo Wellcome Genital HSV & CMV infections Virazole Viratek/ICNasymptomatic HIV Ribavirin (Costa Mesa, CA) positive, LAS, ARC VX-478Vertex HIV infection, AIDS, ARC Zalcitabine Hoffmann-LaRoche HIVinfection, AIDS, ARC, with AZT Zidovudine; AZT Glaxo Wellcome HIVinfection, AIDS, ARC, Kaposi's sarcoma, in combination with othertherapies Tenofovir disoproxil, Gilead HIV infection, fumarate salt(Viread ®) AIDS, (reverse transcriptase inhibitor) Emtriva ®(Emtricitabine) Gilead HIV infection, AIDS, (reverse transcriptaseinhibitor) Combivir ® GSK HIV infection, AIDS, (reverse transcriptaseinhibitor) Abacavir succinate GSK HIV infection, (or Ziagen ®) AIDS,(reverse transcriptase inhibitor) Reyataz ® Bristol-Myers Squibb HIVinfection (or atazanavir) AIDs, protease inhibitor Fuzeon ®Roche/Trimeris HIV infection (or T-20) AIDs, viral Fusion inhibitorLexiva ® GSK/Vertex HIV infection (or Fosamprenavir calcium) AIDs, viralprotease inhibitor Maraviroc; (UK 427857) Pfizer HIV infection AIDs,(CCR5 antagonist, in development) Trizivir ® GSK HIV infection AIDs,(three drug combination) PA-457 Panacos HIV infection AIDs, (maturationInhibitor, in development) Sch-417690 (vicriviroc) Schering-Plough HIVinfection AIDs, (CCR5 antagonist, in development) TAK-652 Takeda HIVinfection AIDs, (CCR5 antagonist, in development) GSK 873140 GSK/ONO HIVinfection ONO-4128) AIDs, (CCR5 antagonist, in development) BMS-707035Bristol-Myers Squibb HIV infection AIDs, (viral integrase Inhibitor)Integrase Inhibitor Merck HIV infection MK-0518 AIDs, viral integraseinhibitor in development Truvada ® Gilead Combination of Tenofovirdisoproxil fumarate salt (Viread ®) and Emtriva ® (Emtricitabine)Integrase Inhibitor Gilead/Japan Tobacco HIV Infection GS917/JTK-303AIDs, viral integrase inhibitor in development Triple drug combinationGilead/Bristol-Myers Squibb Combination of Tenofovir disoproxil fumaratesalt (Viread ®), Emtriva ® (Emtricitabine), and Sustiva ® (Efavirenz)

IMMUNOMODULATORS Drug Name Manufacturer Indication AS-101 Wyeth-AyerstAIDS Bropirimine Pharmacia Upjohn Advanced AIDS Acemannan CarringtonLabs, Inc. AIDS, ARC (Irving, TX) CL246, 738 American Cyanamid AIDS,Kaposi's Lederle Labs sarcoma FP-21399 Fuki ImmunoPharm Blocks HIVfusion with CD4+ cells Gamma Interferon Genentech ARC, in combinationw/TNF (tumor necrosis factor) Granulocyte Genetics Institute AIDSMacrophage Colony Sandoz Stimulating Factor Granulocyte Hoechst-RousselAIDS Macrophage Colony Immunex Stimulating Factor GranulocyteSchering-Plough AIDS, Macrophage Colony combination Stimulating Factorw/AZT HIV Core Particle Rorer Seropositive HIV Immunostimulant IL-2Cetus AIDS, in combination Interleukin-2 w/AZT IL-2 Hoffman-LaRocheAIDS, ARC, HIV, in Interleukin-2 Immunex combination w/AZT IL-2 ChironAIDS, increase in Interleukin-2 CD4 cell counts (aldeslukin) ImmuneGlobulin Cutter Biological Pediatric AIDS, in Intravenous (Berkeley, CA)combination w/AZT (human) IMREG-1 Imreg AIDS, Kaposi's (New Orleans, LA)sarcoma, ARC, PGL IMREG-2 Imreg AIDS, Kaposi's (New Orleans, LA)sarcoma, ARC, PGL Imuthiol Diethyl Merieux Institute AIDS, ARC DithioCarbamate Alpha-2 Schering Plough Kaposi's sarcoma Interferon w/AZT,AIDS Methionine- TNI Pharmaceutical AIDS, ARC Enkephalin (Chicago, IL)MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma Muramyl-Tripeptide GranulocyteAmgen AIDS, in combination Colony Stimulating w/AZT Factor Remune ImmuneResponse Immunotherapeutic Corp. rCD4 Genentech AIDS, ARC RecombinantSoluble Human CD4 rCD4-IgG AIDS, ARC hybrids Recombinant Biogen AIDS,ARC Soluble Human CD4 Interferon Hoffman-La Roche Kaposi's sarcoma Alfa2a AIDS, ARC, in combination w/AZT SK&F106528 Smith Kline HIV infectionSoluble T4 Thymopentin Immunobiology HIV infection Research Institute(Annandale, NJ) Tumor Necrosis Genentech ARC, in combination Factor; TNFw/gamma Interferon

ANTI-INFECTIVES Drug Name Manufacturer Indication Clindamycin withPharmacia Upjohn PCP Primaquine Fluconazole Pfizer Cryptococcalmeningitis, candidiasis Pastille Squibb Corp. Prevention of NystatinPastille oral candidiasis Ornidyl Merrell Dow PCP EflornithinePentamidine LyphoMed PCP treatment Isethionate (IM & IV) (Rosemont, IL)Trimethoprim Antibacterial Trimethoprim/sulfa Antibacterial PiritreximBurroughs Wellcome PCP treatment Pentamidine Fisons Corporation PCPprophylaxis Isethionate for Inhalation Spiramycin Rhone-PoulencCryptosporidial diarrhea Intraconazole- Janssen-Pharm. Histoplasmosis;R51211 cryptococcal meningitis Trimetrexate Warner-Lambert PCPDaunorubicin NeXstar, Sequus Kaposi's sarcoma Recombinant Human OrthoPharm. Corp. Severe anemia Erythropoietin assoc. with AZT therapyRecombinant Human Serono AIDS-related Growth Hormone wasting, cachexiaMegestrol Acetate Bristol-Myers Squibb Treatment of anorexia assoc.W/AIDS Testosterone Alza, Smith Kline AIDS-related wasting Total EnteralNorwich Eaton Diarrhea and Nutrition Pharmaceuticals malabsorptionrelated to AIDS

Additionally, the compounds of the disclosure herein may be used incombination with another class of agents for treating AIDS which arecalled HIV entry inhibitors. Examples of such HIV entry inhibitors arediscussed in DRUGS OF THE FUTURE 1999, 24(12), pp. 1355-1362; CELL, Vol.9, pp. 243-246, Oct. 29, 1999; and DRUG DISCOVERY TODAY, Vol. 5, No. 5,May 2000, pp. 183-194 and Inhibitors of the entry of HIV into hostcells. Meanwell, Nicholas A.; Kadow, John F. Current Opinion in DrugDiscovery & Development (2003), 6(4), 451-461. Specifically thecompounds can be utilized in combination with other attachmentinhibitors, fusion inhibitors, and chemokine receptor antagonists aimedat either the CCR5 or CXCR4 coreceptor.

It will be understood that the scope of combinations of the compounds ofthis disclosure with AIDS antivirals, immunomodulators, anti-infectives,HIV entry inhibitors or vaccines is not limited to the list in the aboveTable but includes, in principle, any combination with anypharmaceutical composition useful for the treatment of AIDS.

Preferred combinations are simultaneous or alternating treatments with acompound of the present disclosure and an inhibitor of HIV proteaseand/or a non-nucleoside inhibitor of HIV reverse transcriptase. Anoptional fourth component in the combination is a nucleoside inhibitorof HIV reverse transcriptase, such as AZT, 3TC, ddC or ddI. A preferredinhibitor of HIV protease is Reyataz® (active ingredient Atazanavir).Typically a dose of 300 to 600 mg is administered once a day. This maybe co-administered with a low dose of Ritonavir (50 to 500 mgs). Anotherpreferred inhibitor of HIV protease is Kaletra®. Another usefulinhibitor of HIV protease is indinavir, which is the sulfate salt ofN-(2(R)-hydroxy-1-(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)—N′-(t-butylcarboxamido)-piperazinyl))-pentaneamideethanolate, and is synthesized according to U.S. Pat. No. 5,413,999.Indinavir is generally administered at a dosage of 800 mg three times aday. Other preferred protease inhibitors are nelfinavir and ritonavir.Another preferred inhibitor of HIV protease is saquinavir which isadministered in a dosage of 600 or 1200 mg tid. Preferred non-nucleosideinhibitors of HIV reverse transcriptase include efavirenz. Thepreparation of ddC, ddI and AZT are also described in EPO 0,484,071.These combinations may have unexpected effects on limiting the spreadand degree of infection of HIV. Preferred combinations include thosewith the following (1) indinavir with efavirenz, and, optionally, AZTand/or 3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT and/orddI and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3)stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and141W94 and 1592U89; (5) zidovudine and lamivudine.

In such combinations the compound of the present disclosure and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

Preferred combinations are simultaneous or alternating treatments ofwith a compound of the present disclosure and an inhibitor of HIVprotease and/or a non-nucleoside inhibitor of HIV reverse transcriptase.An optional fourth component in the combination is a nucleosideinhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddI. Apreferred inhibitor of HIV protease is indinavir, which is the sulfatesalt ofN-(2(R)-hydroxy-1-(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)—N′-(t-butylcarboxamido)-piperazinyl))-pentaneamideethanolate, and is synthesized according to U.S. Pat. No. 5,413,999.Indinavir is generally administered at a dosage of 800 mg three times aday. Other preferred protease inhibitors are nelfinavir and ritonavir.Another preferred inhibitor of HIV protease is saquinavir which isadministered in a dosage of 600 or 1200 mg tid. Preferred non-nucleosideinhibitors of HIV reverse transcriptase include efavirenz. Thepreparation of ddC, ddI and AZT are also described in EPO 0,484,071.These combinations may have unexpected effects on limiting the spreadand degree of infection of HIV. Preferred combinations include thosewith the following (1) indinavir with efavirenz, and, optionally, AZTand/or 3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT and/orddI and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3)stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and141W94 and 1592U89; (5) zidovudine and lamivudine.

In such combinations the compound of the present disclosure and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

Abbreviations

The following abbreviations, most of which are conventionalabbreviations well known to those skilled in the art, are usedthroughout the description of the disclosure and the examples. Some ofthe abbreviations used are as follows:

h = hour(s) rt = room temperature mol = mole(s) mmol = millimole(s) g =gram(s) mg = milligram(s) mL = milliliter(s) TFA = trifluoroacetic AcidDCE = 1,2-Dichloroethane CH₂Cl₂ = dichloromethane TPAP =tetrapropylammonium perruthenate THF = tetrahydofuran DEPBT =3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)- one DMAP =4-dimethylaminopyridine P-EDC = polymer supported1-(3-dimethylaminopropyl)-3- ethylcarbodiimide EDC =1-(3-dimethylaminopropyl)-3-ethylcarbodiimide DMF =N,N-dimethylformamide Hunig's Base = N,N-diisopropylethylamine MCPBA =meta-chloroperbenzoic Acid azaindole = 1H-pyrrolo-pyridine 4-azaindole =1H-pyrrolo[3,2-b]pyridine 5-azaindole = 1H-pyrrolo[3,2-c]pyridine6-azaindole = 1H-pyrrolo[2,3-c]pyridine 7-azaindole =1H-pyrrolo[2,3-b]pyridine PMB = 4-methoxybenzyl DDQ =2,3-dichloro-5,6-dicyano-1,4-benzoquinone OTf =trifluoromethanesulfonoxy NMM = 4-methylmorpholine PIP-COPh =1-benzoylpiperazine NaHMDS = sodium hexamethyldisilazide EDAC =1-(3-dimethylaminopropyl)-3-ethylcarbodiimide TMS = trimethylsilyl DCM =dichloromethane DCE = dichloroethane MeOH = methanol THF =tetrahydrofuran EtOAc = ethyl acetate LDA = lithium diisopropylamideTMP-Li = 2,2,6,6-tetramethylpiperidinyl lithium DME = dimethoxyethaneDIBALH = diisobutylaluminum hydride HOBT = 1-hydroxybenzotriazole CBZ =benzyloxycarbonyl PCC = pyridinium chlorochromate

The compounds of the present disclosure may be administered orally,parenterally (including subcutaneous injections, intravenous,intramuscular, intrasternal injection or infusion techniques), byinhalation spray, or rectally, in dosage unit formulations containingconventional non-toxic pharmaceutically acceptable carriers, adjuvantsand diluents.

Thus, in accordance with the present disclosure, there is furtherprovided a method of treating and a pharmaceutical composition fortreating viral infections such as HIV infection and AIDS. The treatmentinvolves administering to a patient in need of such treatment apharmaceutical composition comprising a pharmaceutical carrier and atherapeutically effective amount of a compound of the presentdisclosure.

The pharmaceutical composition may be in the form of orallyadministrable suspensions or tablets; nasal sprays, sterile injectablepreparations, for example, as sterile injectable aqueous or oleagenoussuspensions or suppositories.

When administered orally as a suspension, these compositions areprepared according to techniques well known in the art of pharmaceuticalformulation and may contain microcrystalline cellulose for impartingbulk, alginic acid or sodium alginate as a suspending agent,methylcellulose as a viscosity enhancer, and sweetners/flavoring agentsknown in the art. As immediate release tablets, these compositions maycontain microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and lactose and/or other excipients, binders,extenders, disintegrants, diluents, and lubricants known in the art.

The injectable solutions or suspensions may be formulated according toknown art, using suitable non-toxic, parenterally acceptable diluents orsolvents, such as mannitol, 1,3-butanediol, water, Ringer's solution orisotonic sodium chloride solution, or suitable dispersing or wetting andsuspending agents, such as sterile, bland, fixed oils, includingsynthetic mono- or diglycerides, and fatty acids, including oleic acid.

The compounds of this disclosure can be administered orally to humans ina dosage range of 1 to 100 mg/kg body weight in divided doses. Onepreferred dosage range is 1 to 10 mg/kg body weight orally in divideddoses. Another preferred dosage range is 1 to 20 mg/kg body weight individed doses. It will be understood, however, that the specific doselevel and frequency of dosage for any particular patient may be variedand will depend upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the age, body weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination, theseverity of the particular condition, and the host undergoing therapy.

Chemistry

The present disclosure comprises compounds of Formula I, theirpharmaceutical formulations, and their use in patients suffering from orsusceptible to HIV infection. The compounds of Formula I includepharmaceutically acceptable salts thereof. General procedures toconstruct compounds of Formula I and intermediates useful for theirsynthesis are described in the following Schemes.

Preparation of Compounds of Formula I

A chemist skilled in the art is aware of many standard conditions forreacting an amine with an acyl halide 1 (Scheme 1) and carboxyl acid 4(Scheme 2) that could be used to convert the acid chloride or acid tothe desired amide products. Some general references of thesemethodologies and directions for use are contained in “ComprehensiveOrganic Transformation” by Richard C. Larock, Wiley-VCH, New York, 1989,972 (Carboxylic acids to amides), 979 (Acid halides to amides).

Scheme 1 depicts a general method for forming an amide from piperidinealkene 2 and acyl chloride 1. An appropriate base (from catalytic to anexcess amount) selected from sodium hydride, potassium carbonate,triethylamine, DBU, pyridine, DMAP or di-isopropyl ethyl amine was addedinto a solution of agent 2 and acyl chloride in an appropriate solventselected from dichloromethane, chloroform, benzene, toluene, THF,diethyl ether, dioxane, acetone, N,N-dimethylformamide or pyridine atroom temperature. The reaction was carried out at either roomtemperature or experimentally determined optimum temperature up to 150°C. over a period of time (30 minutes to 16 hours) to afford compounds 3which may either be compounds of formula I or precursors. Some selectedreferences involving such reactions include a) Indian J. Chem., Sect B1990, 29, 1077; 2) Chem. Sci. 1998, 53, 1216; 3) Chem. Pharm. Bull.1992, 40, 1481; 4) Chem. Heterocycl. Compd. 2002, 38, 539.

Alternatively, as shown in Scheme 2, structure 2 can be coupled with anacid 4 using standard amide bond or peptide bond forming couplingreagents. Many reagents for amide bond couplings are known by an organicchemist skilled in the art and nearly all of these are applicable forrealizing coupled amide products. The combination of EDAC andtriethylamine in tetrahydrofuran or BOPCl and diisopropyl ethyl amine inchloroform have been utilized most frequently but DEPBT, or othercoupling reagents such as PyBop could be utilized. Another usefulcoupling condition employs HATU ((a) J. Chem. Soc. Chem. Comm. 1994,201; (b) J. Am. Chem. Soc. 1994, 116,11580). Additionally, DEPBT(3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one) andN,N-diisopropylethylamine, commonly known as Hunig's base, representsanother efficient method to form the amide bond and provide compounds ofFormula I. DEPBT is either purchased from Adrich or prepared accordingto the procedure described in Organic Lett., 1999, 1, 91. Typically aninert solvent such as DMF or THF is used but other aprotic solventscould be used.

The general agent 2 used in Schemes 1 and 2, are either commerciallyavailable or may be prepared according to procedures described in detailin US-2004/0063744.

Scheme 3 describes a general route towards the structure of intermediate4. Alcohol 5 couples with a t-butyl 2-halo propanioc ester with a baseselected from NaH, KH, LiHMDS, NaHMDS, KHMDS, Li₂CO₃, Na₂CO₃, K₂CO₃,Ce₂CO₃ in an aprotic solvent. Typically an inert solvent such as DMF,THF, DME, dioxane, DMSO is used but other aprotic solvents could beused. The Boc group is removed under acidic solution would provide a2-keto piperazine amide intermediate. TFA and HCl are the typicalsolvents, while the most commonly used solvents are ether anddichloromethane, but other acidic agents and solvents could be used.

As shown in Scheme 4, intermediate 1 can be prepared from intermediate 4by using SOCl₂, ClCOCOCl or POCl₃ with or without solvent. When asolvent is used, typical solvent is CH₂Cl₂ or ClCH₂CH₂Cl, but otheraprotic solvents could be used.

EXAMPLES

The following examples illustrate typical syntheses of the compounds ofFormula I as described generally above. These examples are illustrativeonly and are not intended to limit the disclosure in any way. Thereagents and starting materials are readily available to one of ordinaryskill in the art.

Chemistry

Typical Procedures and Characterization of Selected Examples:

Unless otherwise stated, solvents and reagents were used directly asobtained from commercial sources, and reactions were performed under anitrogen atmosphere. Flash chromatography was conducted on Silica gel 60(0.040-0.063 particle size; EM Science supply). ¹H NMR spectra wererecorded on Bruker DRX-500f at 500 MHz (or Bruker DPX-300B or VarianGemini 300 at 300 MHz as stated). The chemical shifts were reported inppm on the δ scale relative to δTMS=0. The following internal referenceswere used for the residual protons in the following solvents: CDCl₃(δ_(H) 7.26), CD₃OD (δ_(H) 3.30), and DMSO-d6 (δ_(H) 2.50). Standardacronyms were employed to describe the multiplicity patterns: s(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), b(broad), app (apparent). The coupling constant (J) is in Hertz. AllLiquid Chromatography (LC) data were recorded on a Shimadzu LC-10ASliquid chromatograph using a SPD-10AV UV-Vis detector with MassSpectrometry (MS) data determined using a Micromass Platform for LC inelectrospray mode.

Analytical LC-MS Method:

Method A:

-   Column A: Xterra 2.1×50 mm 5 um C18-   Solvent: A=Water, B=ACN, Modifier=10 mM NH₄OAc-   Gradient: 0.00′=10% B, 0.80′=60% B, 1.99′=95% B, 2.00′ (1.5    mL/min)=100%-   B, 2.56′=100% B, 2.74′=10% B-   Flow rate: 1 ml/min-   Detector Wavelength: 220 nm    Method B:-   Column B: Phenomenex-Luna 4.6×50 mm S10-   Start % B=0-   Final % B=100-   Solvent: A=10% MeOH/90% H2O/0.1% TFA-   Solvent: B=90% MeOH/10% H2O/0.1% TFA-   Gradient time: 4 min-   Flow rate: 4 ml/min-   Detector Wavelength: 220 nm    HPLC Purification Method:

Compounds purified by preparative HPLC were diluted in DMF (1.5 ml) andpurified using the following methods on a Waters automated preparativeHPLC system.

-   Column C: Xbridge 19×50 mm 5 um C18-   Solvent: A=Water, B=ACN, Modifier=10 mM NH₄OAc-   Method: 25 mL/min, 0′=10% B, 0.5′ (12.5 mL/min)=10% B, 2′ (12.5    mL/min)=10% B, 2.5′=10% B, 9.3′=95% B, 12′=95% B-   Detector Wavelength: 220 nm    Preparation of Agent A:-   (1) Preparation of 2-(quinolin-5-yloxy)propanoic acid (A01):

Quinolin-5-ol (0.868 g, 5.98 mmol) and tert-butyl 2-bromopropanoate(1.25 g, 0.97 mL, 5.98 mmol) and cesium carbonate (1.95 g, 5.98 mmol)were added into DMF (10 mL) in a 20 mL microwave vial equipped with astir bar and sealed. The mixture was heated in Biotage microwavesynthesizer for 1 hour at 100° C. The solvent was removed and theremained sticky oil was dissolved in DCM (7 mL) and TFA (7 mL). Themixture was stirred overnight. The reaction mixture was neutralized withsodium bicarbonate and organic layer was separated from the mixture. Theaqueous layer washed with DCM (2×10 mL), combined organics and acidifiedwith 2N HCl. Aqueous was extracted with ethyl acetate, dried with sodiumsulfate and concentrated to a dark orange oil. The crude product wasdissolved in DCM (4 mL) and a pure product (0.855 g) precipitate outfrom the solution by adding diethyl ether (4 mL).

-   (2) Preparation of 2-(2-methoxy-4-(methoxycarbonyl)phenoxy)propanoic    acid (A02):

Methyl 4-hydroxy-3-methoxybenzoate (1.09 g, 5.98 mmol) and tert-butyl2-bromopropanoate (1.25 g, 0.97 mL, 5.98 mmol) and cesium carbonate(1.95 g, 5.98 mmol) were added into DMF (10 mL) in a 20 mL microwavevial equipped with a stir bar and sealed. The mixture was heated inBiotage microwave synthesizer for 1 hour at 100° C. The solvent wasremoved and the remained sticky oil was dissolved in DCM (7 mL) and TFA(7 mL). The mixture was stirred overnight. The reaction mixture wasneutralized with sodium bicarbonate and organic layer was separated fromthe mixture. The aqueous layer washed with DCM (2×10 mL), combinedorganics and acidified to around pH5 with 2N HCl. Aqueous was extractedwith DCM and then with ethyl acetate, dried with sodium sulfate andconcentrated to an oil. The crude product was dissolved in DCM (4 mL)and a pure product (0.530 g) precipitate out from the solution by addingdiethyl ether (4 mL).

MS (M + H)⁺ MS (M + H)⁺ Observ./Retention Structure Calcd. Time/NMR A-01

218.08 218.24 Rf = 1.15 min (column B) ¹H NMR (500 MHz, DMSO-d₆) δ 9.06(m, 1H), 8.85 (d, 1H), 7.68-7.81 (m, 3H), 7.06 (d, 1H), 5.16 (q, 1H),1.67 (d, 3H). A-02

255.09 255.24 Observed. Rf = 2.36 min (column A) ¹H NMR (500 MHz,DMSO-d₆) δ 13.13 (b, 1H), 7.53 (m, 1H), 7.47 (m, 1H), 4.91 (m, 1H), 3.81(d, 3H), 1.52 (d, 3H).Preparation of Compound of Formula IA general procedure, exemplified by the following reaction:

2-(quinolin-5-yloxy)propanoic acid, A01 (23.3 mg, 92 umol), TBTU (32.8mg, 102 umol) and DIPEA (35.7 mg, 276 umol) in DMF (1 mL) were addedinto a 1-dram vial, followed by addition of2-phenyl-2-(piperidin-4-ylidene) acetonitrile in DMF (0.5 mL). The vialwas capped and shaken at room temperature overnight. The reaction wasmonitored by the following analytical LC-MS method and the product waspurified by prep-HPLC using the following HPLC purification method.

MS (M + H)⁺ MS (M + H)⁺ Observ./HPLC Structure Calcd. Retention Time/NMR

398.19 398.21 Rf = 1.34 min (column A) ¹H NMR (500 MHz, CDCl₃) δ9.28-9.32 (m, 1H), 9.01 (s, 1H), 8.46 (m, 1H), 7.91 (m, 2H), 7.30-7.38(m, 5H), 7.07 (m, 1H), 5.36 (m, 1H), 3.82 (m, 2H), 3.62 (m, 2H),2.70-2.83 (m, 2H), 2.41-2.50 (m, 2H), 1.82 (m, 3H)

412.20 412.21 Rf = 1.28 min (column A)

449.20 449.23 Rf = 1.6 min (column A)

450.22 450.21 Rf = 1.24 min (column A)

455.21 455.21 Rf = 1.26 min (column A)

435.19 435.22 Rf = 1.41 min (column A)

449.21 449.22 Rf = 1.36 min (column A)

486.23 486.23 Rf = 1.66 min (column A)

487.22 487.22 Rf = 1.29 min (column A)

492.21 492.26 Rf = 1.23 min (column A)

412.19 412.23 Rf = 1.26 min (column A)

Biology

-   “μM” means micromolar;-   “mL” means milliliter;-   “μl” means microliter;-   “mg” means milligram;

The materials and experimental procedures used to obtain the resultsreported in Tables 1-2 are described below.

Cells:

Virus production-Human embryonic Kidney cell line, 293T, was propagatedin Dulbecco's Modified Eagle Medium (Invitrogen, Carlsbad, Calif.)containing 10% fetal Bovine serum (FBS, Sigma, St. Louis, Mo.).

Virus infection-Human epithelial cell line, HeLa, expressing the HIV-1receptor CD4 was propagated in Dulbecco's Modified Eagle Medium(Invitrogen, Carlsbad, Calif.) containing 10% fetal Bovine serum (FBS,Sigma, St. Louis, Mo.) and supplemented with 0.2 mg/mL Geneticin(Invitrogen, Carlsbad, Calif.).

Virus-Single-round infectious reporter virus was produced byco-transfecting human embryonic Kidney 293 cells with an HIV-1 envelopeDNA expression vector and a proviral cDNA containing an envelopedeletion mutation and the luciferase reporter gene inserted in place ofHIV-1 nef sequences (Chen et al., Ref 41). Transfections were performedusing lipofectAMINE PLUS reagent as described by the manufacturer(Invitrogen, Carlsbad, Calif.).

Experiment:

HeLa CD4 cells were plated in 96 well plates at a cell density of 1×10⁴cells per well in 100 μl Dulbecco's Modified Eagle Medium containing 10%fetal Bovine serum and incubated overnight.

Compound was added in a 2 μl dimethylsulfoxide solution, so that thefinal assay concentration would be ≦10 μM.

100 μl of single-round infectious reporter virus in Dulbecco's ModifiedEagle Medium was then added to the plated cells and compound at anapproximate multiplicity of infection (MOI) of 0.01, resulting in afinal volume of 200 μl per well.

Virally-infected cells were incubated at 37 degrees Celsius, in a CO₂incubator, and harvested 72 h after infection.

Viral infection was monitored by measuring luciferase expression fromviral DNA in the infected cells using a luciferase reporter gene assaykit, as described by the manufacturer (Roche Molecular Biochemicals,Indianapolis, Ind.). Infected cell supernatants were removed and 50 μlof lysis buffer was added per well. After 15 minutes, 50 μl offreshly-reconstituted luciferase assay reagent was added per well.Luciferase activity was then quantified by measuring luminescence usinga Wallac microbeta scintillation counter.

The percent inhibition for each compound was calculated by quantifyingthe level of luciferase expression in cells infected in the presence ofeach compound as a percentage of that observed for cells infected in theabsence of compound and subtracting such a determined value from 100.

An EC₅₀ provides a method for comparing the antiviral potency of thecompounds of this disclosure. The effective concentration for fiftypercent inhibition (EC₅₀) was calculated with the Microsoft Excel Xlfitcurve fitting software. For each compound, curves were generated frompercent inhibition calculated at 10 different concentrations by using afour paramenter logistic model (model 205). The EC₅₀ data for thecompounds is shown in Table 2. Table 1 is the key for the data in Table2.

Results:

TABLE 1 Biological Data Key for EC₅₀s Compounds with Compounds withEC₅₀s > 1 μM EC₅₀ <= 1 μM Group B Group A

TABLE 2 EC₅₀ Group from Structure Table 1

A

A

B

B

B

A

A

A

B

A

A

1. A compound defined by the following formula, or pharmaceuticallyacceptable salts thereof:


2. A pharmaceutical composition which comprises an antiviral effectiveamount of the compound, or pharmaceutically acceptable salts thereof, asclaimed in claim 1, and one or more pharmaceutically acceptablecarriers, excipients or diluents.
 3. The composition of claim 2 furthercomprising a second compound having anti-HIV activity.
 4. Thepharmaceutical composition of claim 2, useful for treating infection byHIV, which additionally comprises an antiviral effective amount of anAIDS treatment agent selected from the group consisting of: (a) an AIDSantiviral agent; (b) an anti-infective agent; (c) an immunomodulator;and (d) HIV entry inhibitors.